Diffuse large B-cell lymphoma (DLBCL) is recognized as a heterogeneous disease with distinct subgroups delineated via gene expression profiling. The anti-apoptosis gene BCL2, located at chromosome 18q21, is frequently over-expressed in DLBCL, but there were previously conflicting data regarding its utility as a prognostic marker. Iqbal and colleagues correlated BCL2 protein expression with survival in DLBCL cases previously stratified into the two major subgroups of germinal center B-cell-like (GCB) and activated B-cell-like (ABC). They also investigated whether BCL2 expression occurred via the chromosomal translocation t(14;18)(q32;q21) or via chromosome 18q21 gain or amplification. BCL2 was expressed in half of the GCB cases, usually via the t(14;18), but had no correlation with overall survival. In contrast, BCL2 expression in the ABC cases was demonstrated in 59 percent of cases and was strongly associated with poorer survival (Figure). This correlation held even with use of differing cutoff limits for positivity in BCL2 expression. Unlike GCB, BCL2 expression in the ABC subgroup was associated with 18q21 gain or amplification but in no instance with the t(14;18) (Table).
In Brief
DLBCL is the most common lymphoma in Western countries. While about half of all patients are cured by initial therapy, the remainder either progress after initial response or are primarily refractory. Understandably, there is considerable interest in identifying biomarkers of response or resistance which might improve prognostic and therapeutic stratification for these patients. BCL2 has been extensively evaluated in this regard due to its role in promoting cell survival and chemotherapy resistance, but with inconclusive results. The report by Iqbal et al. clarifies previously conflicting data by associating expression with DLBCL subgroup. Importantly, BCL2 expression in ABC lymphomas is associated with chromosome 18q21 gain or amplification, and perhaps with upregulation of NFkB or other regulatory pathways. It is as yet unclear whether BCL2 expression directly contributes to the observed poorer survival in the ABC group or is instead a marker for other co-amplified genes at 18q21, downstream targets of these molecules, or NFkB itself. This study supports the classification of clinical responses by tumor subgroup in ongoing and future DLBCL clinical trials. Investigations of lymphoma pathogenesis, biomarkers of therapeutic response and resistance, and the identification of potential therapeutic targets now have new leads to pursue.
